At the Cutting EdgeThe anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis
Introduction
Glucocorticoids exert a dramatic effect on a variety of mammalian cells. This class of steroid hormones alters both cellular metabolism and gene expression and has long been known to display cytotoxic effects on certain cell types, such as lymphocytes (Munck et al., 1981). Glucocorticoids released from the adrenal gland during periods of stress lead to the catabolism of proteins, lipids, and carbohydrates, and result in an increase in blood sugar (Keller et al., 1983, Homo-Delarche et al., 1991). Glucocorticoids repress or activate gene transcription through interaction with the glucocorticoid receptor (GR) (Cidlowski et al., 1996). The immune system is exquisitely sensitive to the lytic action of glucocorticoids as well as to their metabolic and genetic actions (Cidlowski et al., 1996). Since the complex physiological processes involved in mammalian immune and inflammatory responses are critical for the homeostasis and for the ultimate survival of an organism, their coordinate regulation must assure an appropriate and timely immune reaction without an overreaction that might damage the host (McKay et al., 1999).
It has been known for the last decade that glucocorticoids induce apoptosis in most nucleated cells of the vascular system, such as thymocytes, myeloma cells and peripheral blood monocytes (Table 1; Dowd et al., 1992, Sikora et al., 1996, Chauhan et al., 1997, Schmidt et al., 1999), thus playing a central anti-inflammatory role. Recently, there is increasing evidence for a complementary action of glucocorticoids in protecting the cells, tissues and organs in which the inflammation takes place. This phenomenon raise intriguing questions:
- 1
What is the impact of the cell origin (lineage) and final phenotype on the glucocorticoid effect on apoptosis?
- 2
Does the anti-apoptotic action of glucocorticoids involve expression or attenuation of the same or different gene products which are involved in their pro-apoptotic action?
- 3
Is the anti-apoptotic effect of glucocorticoids mediated by the same receptor as their pro-apoptotic effect?
Section snippets
The glucocorticoid receptor and apoptosis
Most of the effects of glucocorticoids in controlling the apoptotic process in various cell types are believed to be mediated by the GR (Evans-Storms et al., 1995).
Two GR isoforms were characterized recently in human cells, both in health and disease (Cidlowski et al., 1996, Moutsatsou et al., 2000). However, all receptor activity was attributed to the α isoform of GR (GRα). It is not yet clear whether GRβ, which is able to inhibit the activity of GRα, is involved in glucocorticoid induced
Activation of genes involved in apoptosis
Some of the most active genes involved in both induction and prevention of apoptosis, are the members of the Bcl-2 family (Chao et al., 1998, Bergmann et al., 1998). The family consists of proteins which are pro-apoptotic, such as Bcl-xS, Bad, Bax, Bid, and anti-apoptotic, such as Bcl-2, Mcl-1 and Bcl-xL (Nagata, 1997). The various Bcl-2 family members can dimerize with a homologue or heterologue monomer enhancing or antagonizing the function of the other. In this way, the ratio of inhibitors
Mammary gland
Dexamethasone, a stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in the mouse mammary gland (Feng et al., 1995). Injection of Dex led to milk accumulation and was accompanied by an induction of protein kinase A, elevated c-fos, jun B and junD mRNA levels and AP-1 DNA binding activity. Potential target genes of AP-1 such as stromelysin-1, c-jun and SGP-2, which are induced during normal involution, were strongly inhibited in Dex-treated animals.
Anti-apoptotic effect of glucocorticoids: implication in health and disease
Glucocorticoids, among the most widely prescribed compounds in current medical practice, are invaluable in the treatment of inflammatory disorders and pulmonary insufficiency during the prenatal period (Cosmi et al., 1989). These hormones induce apoptosis in lymphocytes and are therefore used as chemotherapeutic agents against many leukemias (Schwartzman et al., 1993, Smets et al., 1999). In contrast, glucocorticoids suppress spontaneous apoptosis of neutrophils, TNFα mediated apoptosis of
Conclusions
The effect of glucocorticoids on apoptosis is dramatically depends on the cell lineage. It seems that cells of hematopoietic origin such as monocytes, macrophages, lymphocytes and lymphoma cells are very sensitive to glucocorticoid stimulation of apoptosis. In contrast, cells of epithelial origin, such as mammary gland, ovarian follicular cells and hepatocytes as well as transformed epithelial cell, such as hepatoma cells and gastric cancer cells are protected by glucocorticoid against various
Acknowledgments
We thank Professors A.M. Kaye and M. Liscovitch for helpful discussion, Dr. K. Tajima for excellent assistance in the graphic work and A.L. Greninger for his assistance in editing and typing the manuscript. The authors work was partially supported by grants from the Yad Abraham Research Center for Cancer Diagnosis and Therapy and Levin Center for Applied Research at the Weizmann Institute of Science, Rehovot, Israel.
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